Of Beta Oxidation Of Fatty Acids Three Stages Of Beta Oxidation For Oxidation Fatty acid Palmitate Stage I Activation of Long Chain Fatty acid Acyl Chain To AcylCoA In Cytosol ID: 913876
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Slide1
LIPID METABOLISM
Slide2Stages And Reaction Steps
Of Beta Oxidation Of Fatty Acids
Slide3Three Stages
Of Beta Oxidation
For
Oxidation Fatty
acid Palmitate
Slide4Stage I
Activation of
Long Chain Fatty acid (Acyl
Chain
)
To
Acyl-CoA In Cytosol
Palmitate to Palmitoyl-CoA
In Cytosol
Slide5Stage II
Translocation
of Activated Fatty acid
From
Cytosol into Mitochondrial Matrix
Through
Role
of Carnitine
(Carnitine Shuttle)
Slide6Stage III
Steps
of Beta Oxidation
Proper
In Mitochondrial Matrix
Oxidation Reaction
Hydration Reaction
Oxidation Reaction
Cleavage Reaction
Slide7Stage I
Activation Of Fatty acid
In Cytosol
Is a Preparative Phase
Slide8Site Of Fatty
acid Activation
Fatty acid(Acyl Chain) is activated in
Cytosol
to
Acyl-CoA
.
Slide9Requirements of FA Activation
Enzyme:
Thiokinase
/
Acyl CoA Synthe
tase
Coenzymes/Cofactors:
CoA-SH
derived from Pantothenic acid
ATP
Magnesium ions (
Mg
++
)
Slide10CoezymeA (CoA-SH)
Activates
Fatty Acids
for Beta Oxidation
Slide11CoA Helps in
Activation of Fatty Acid
Slide12A
long chain
Fatty acid is termed as
Acyl chain.
Every Fatty acid
which undergoes
β
Oxidation of Fatty acid is
first activated
to
Acyl-CoA.
Slide13Activation
of
a
Fatty
acid
means:
Linking of
Acyl Chain
to
Coenzyme A
to form
Acyl
-
CoA with a high energy bond.
Slide14During Activation of
Fatty acid (Acyl Chain)
‘
H
’
of
CoA-S
H (Coenzyme A)
is
substituted by
Acyl
chain
To form
CoA-S Acyl,
i.e.
Acyl-
CoA
an activated Fatty acid.
Slide15Thus
CoenzymeA
is a
carrier of Acyl chain
in
an
activated fatty acid.
Slide16Steps Of Fatty Acid Activation
Slide17Activation Of a Fatty Acid
Is ATP Dependent
Converts ATP to AMP
Hence Requirement is equivalent to 2 ATPs
Slide18Slide19Slide20Acyl-CoA
Synthetase/
Fatty
Acid Thiokinase
condenses Fatty acids with CoA,
with
simultaneous hydrolysis of ATP to AMP and PP
i
Slide21A
n
Acyl-CoA is an
activated energetic compound
having
high energy
bond in it.
Slide22Thus formation
of
Acyl–CoA is an
expensive
energetically
Slide23Fatty acid
Activation
Activation of Fatty acids is
esterification of Fatty acid with Coenzyme
A
In
presence of
Acyl-CoA
Synthetase
(
Thiokinase
)
forming an activated Fatty acid as Acyl-CoA.
This process is
ATP-dependent
, & occurs in
2 steps.
Slide24During the activation of Fatty acid
ATP is converted to AMP and
ppi
.
Two high energy bonds
of
ATP
are
cleaved
and
utilized
in this activation which is
equivalent to 2 ATPs.
Slide25Subsequent
hydrolysis of PP
i
from ATP drives
the
reaction strongly
forward.
Note the
Acyl- Adenylate
is an
intermediate
in the mechanism.
Slide26There are
different Acyl-CoA
Synthetase
for fatty acids of
different chain lengths
.
Slide27Activated Fatty Acid (Acyl-CoA)
is a High Energy Compound
Which Facilitates
Second
Stage
Of
Beta Oxidation Of Fatty Acid
Slide28Stage II
Translocation Of Acyl-CoA
From Cytosol
Into Mitochondrial Matrix
With The Help Of Carnitine
Slide29β-oxidation proper occurs
in
Mitochondrial
matrix.
CoA is a complex structure
.
CoA
part of
Palmitoyl-CoA
is
impermeable to inner membrane of Mitochondria
Slide31Long-chain
F
atty
acids
more than 12 Carbon atoms
cannot
be directly
translocated
into the M
itochondrial matrix.
However
short
chain Fatty acids are directly translocated into the Mitochondrial matrix
Slide32To
translocate
an
activated
long chain Fatty
acid
(Acyl-CoA) from
cytosol
to
mitochondrial
matrix
Across
mitochondrial
membrane operates a specialized Carnitine Carrier System.
Slide33What Is Carnitine?
Carnitine
is a
functional
,
Non Protein Nitrogenous
(NPN) substance.
Carnitine is
biosynthesized
in the body
by amino acids
Lysine and Methionine
.
Slide34Carnitine
chemically
is
Hydroxy- γ Tri Methyl
Ammonium Butyrate
OR
3-Hydroxy
4- Tri Methyl
Ammonium
Butyrate
Long chain Acyl CoA
traverses
an
inner mitochondrial
membrane with a
special transport mechanism
called
Carnitine Shuttle
.
Slide36Significance Of Acyl-CoA Formation
High energy bond of Acyl-CoA releases high energy which helps in condensation of Acyl with Carnitine for further translocation.
Slide37Mechanism Of Carnitine
In Transport Of
Fatty
Acyl CoA
From Cytosol To Mitochondrial Matrix
Slide38Slide39Slide40Slide41Slide42Acyl-CoA a high energy compound
cleave its high energy bond in
second
stage.
B
ond
energy released is used up for
linking
Carnitine
to Acyl chain to form Acyl-Carnitine.
Slide43Long-chain FA
are converted to
Acyl Carnitine
and are then transported
Acyl-CoA
are
reformed
inside
an
inner membrane of mitochondrial
matrix.
Slide44Acyl groups from
Acyl-COA
is transferred to
C
arnitine to form
Acyl-
Carnitine catalyzed by
Carnitine Acyl Transferase
I
(CAT I)
CAT I is present associated to outer mitochondrial membrane
.
Acylcarnitine
is then shuttled across
an
inner mitochondrial membrane by
a
T
ranslocase
enzyme.
Acyl
group
is
linked
to
CoA of
Mitochondrial
pool
in mitochondrial matrix by
Carnitine Acyl Transferase
II (CAT II) to regenerate Acyl-CoA in mitochondrial matrix.
Finally, Carnitine is returned
to
cytosolic side by
P
rotein Translocase
, in exchange for an incoming Acyl Carnitine.
Slide46Points To Remember
Cell maintains two separate pools of Coenzyme-A:
Cytosolic pool of CoA
Mitochondrial pool of CoA
Slide47CoA is complex structure
cannot transport across
Mitochondrial membrane
CoA
linked to Fatty acid in
Mitochondria
is different from that CoA used for Fatty acid activation.
Slide48Translocation of
Palmitoyl-CoA
Across
Mitochondrial Membrane
Slide49Activation of P
almitate
to P
almitoyl
CoA
and
conversion to P
almitoyl
C
arnitine
Intermembrane
Space
OUTER
MITOCHONDRIAL
MEMBRANE
palmitoyl-carnitine
CoA
palmitoyl-CoA
carnitine
Cytoplasm
palmitoyl-CoA
AMP + PP
i
ATP + CoA
palmitate
CPT-I
[2]
ACS
[1]
Slide50Mitochondrial
uptake via of
Palmitoyl-
C
arnitine
via the
Carnitine-
A
cylcarnitine Translocase
(CAT)
Matrix
INNER
MITOCHONDRIAL
MEMBRANE
Intermembrane Space
P
almitoyl-
C
arnitine
C
arnitine
CoA
palmitoyl-CoA
CAT
[3]
palmitoyl-carnitine
CPT-II
C
arnitine
CoA
palmitoyl-CoA
[4]
CPT-I
Slide51CAT
Intermembrane
Space
OUTER
MITOCHONDRIAL
MEMBRANE
palmitoyl-carnitine
CoA
Carnitine
Cytoplasm
palmitoyl-CoA
AMP + PP
i
ATP + CoA
palmitate
palmitoyl-CoA
Matrix
INNER
MITOCHONDRIAL
MEMBRANE
[3]
palmitoyl-carnitine
carnitine
CoA
palmitoyl-CoA
[4]
CPT-I
[2]
ACS
[1]
CPT-II
Slide52Carnitine-mediated transfer of the
fattyAcyl
moiety into the mitochondrial matrix is a 3-step process:
1.
Carnitine Palmitoyl Transferase I
, an enzyme on the cytosolic surface of the outer mitochondrial membrane, transfers a fatty acid from CoA to the OH on C
arnitine
.
2.
An
Translocase
/
Antiporter
in the inner mitochondrial membrane mediates exchange of C
arnitine
for
Acylcarnitine
.
Slide533.
Carnitine Palmitoyl Transferase II
, an enzyme within the matrix, transfers the fatty acid from C
arnitine
to CoA. (Carnitine exits the matrix in step 2.)
The fatty acid is now esterified to CoA in the
mitochondrial matrix
.
Slide54Stage III
Steps
of Beta Oxidation
Proper/Cycle
In Mitochondrial Matrix
Oxidation Reaction
Hydration Reaction
Oxidation Reaction
Cleavage Reaction
Slide55Site/Occurrence Of
β
–
Oxidation
Proper
I
n
Mitochondrial
M
atrix
of Cells.
After
translocation of Acyl-CoA
in Mitochondrial matrix
.
Slide56Mechanism Of Reactions
Of
Beta Oxidation Proper
of
Palmitoyl-CoA
Slide57Slide58Step I
:
Oxidation
by
FAD
linked
Acyl
CoA Dehydrogenase
Step II
:
Hydration
by
Enoyl CoA
Hydratase
Step III
: Oxidation
by
NAD linked
β
eta Hydroxy Acyl CoA Dehydrogenase
Step IV
: Thiolytic
Cleavage by
Keto Thiolase
Slide59Slide60Slide61
-Oxidation
of P
almitoyl
CoA
matrix side
inner mitochondrial
membrane
1.5
ATP
2.5
ATP
respiratory chain
recycle
6 times
Carnitine
translocase
Palmitoylcarnitine
Palmitoylcarnitine
Palmitoyl-CoA
+ Acetyl CoA
CH
3
-(CH)
12
-C-S-CoA
O
oxidation
FAD
FADH
2
hydration
H
2
O
cleavage
CoA
oxidation
NAD
+
NADH
Citric
acid
cycle
2 CO
2
Slide62Slide63Strategy of
First 3 reactions
of Beta Oxidation proper is to
Create
a
Carbonyl
group
(C=O) on
-
Carbon atom (CH2)
of a Fatty acid.
This
weakens
bond
between
α
and
β
Carbon
atoms
of Fatty acid.
Fourth reaction
cleaves
"
-
K
eto
ester"
in a
reverse Claisen condensation reaction.
Slide65Products
of Each turn/cycle of
beta oxidation
proper are
:
Acetyl-CoA
Acyl-CoA
with
two carbons shorter
Slide66Slide67Step
1
Role Of
Acyl-CoA
Dehydrogenase
To Bring
Oxidation
of the C
-C
bond
of Fatty acid
Slide68Acyl CoA Dehydrogenase
is a
FAD linked
Enzyme
(Flavoprotein)
Slide69Acyl CoA Dehydrogenase
catalyzes Oxidation reaction
Where there is a
removal of Hydrogen
from
alpha and beta carbon atoms
of Acyl-CoA.
Slide70There
forms a double bond
between
C
α
-
C
β
/
C2 and C3
of Fatty Acid.
The product of this oxidation reaction is
α-β Unsaturated Acyl CoA
/
Trans Enoyl CoA.
Slide71Coenzyme
FAD
is the
temporary hydrogen
acceptor
in this oxidation reaction
.
The
reduced FADH2
is generated by oxidation reaction of Acyl CoA
Dehydrogenase.
FADH2
is then
reoxidized, after its enter into Electron Transport Chain
Slide72Mechanism of Acyl CoA Dehydrogenase involves :
Proton
Abstraction/Removes
Hydrogen
Double bond formation
Hydride removal by FAD
Generation of
reduced FADH2
Slide73FADH2 is oxidized
by entering into
ETC.
Electrons
from
FADH2 are passed to
Electron
transport
chain components
,
Coupled with phosphorylation to
generate
1.5
ATP
(By Oxidative Phosphorylation).
Slide75Slide76Slide77Acyl-CoA Dehydrogenase
Slide78There are
different
Acyl-CoA Dehydrogenases
:
S
hort Chain Fatty acids
(4-6 C),
Medium Chain Fatty Acids
(6-10 C
),
Long
(12-18 C)
and very long
(22 and more)chain Fatty
acids.
Slide79Inhibitor Of
Acyl CoA Dehydrogenase
Acyl CoA Dehydrogenase is
inhibited by
a
Hypoglycin
(from
Akee fruit
)
Slide80Step
2
Role Of
Enoyl CoA Hydratase
To add
water across the
double
bond
C
α
= C
β
of Trans-Enoyl-CoA
Saturate the double bond of Enoyl-CoA
Generate Hydroxyl group at beta carbon
Slide81Enoyl-CoA Hydratase
catalyzes stereospecific
hydration
of the trans double bond
It adds
water across the double bond
at C2 and C3
of
Trans Enoyl CoA
Slide82This
hydration reaction
generates Hydroxyl (
OH) group
at beta carbon atom of FA
Converts
Trans-Enoyl-CoA
to
L
β-Hydroxyacyl-CoA
Slide83Slide84Slide85Slide86Step
3
Role Of
Hydroxyacyl-CoA
Dehydrogenase
To Oxidizes
the
-Hydroxyl Group
of
β-
Hydroxyacyl
-CoA
And
Transform it into
β-Ketoacyl-CoA
β
-Hydroxyacyl-CoA
Dehydrogenase
is NAD
+
dependent
It catalyzes
specific oxidation of the Hydroxyl
group in
the
b
position (C3)
to form
a ketone group
.
NAD
+
is the
temporary electron
acceptor for this step which generates
reduced form
NADH+H
+
Slide88The
oxidation
of
β
-Hydroxyacyl
CoA
produces a product
β
- Ketoacyl-CoA.
Slide89Slide90Slide91Slide92Step
4
Role Of
b
- Ketothiolase /Thiolase
Catalyzes
Thiolytic
cleavage
of the
two
carbon
fragment
by
splitting the
bond
between
α
and
β
carbons
Slide93An enzyme
-
Keto Thiolase attacks
the
-carbonyl group
of
β
-
Ketoacyl
-CoA
.
This results
in the
cleavage of
the
C
α
-C
β
bond.
Releases
Acetyl-CoA
(2C
) and an
Acyl-CoA
(-
2carbons shorter ).
Slide94Slide95Slide96Slide97Slide98Slide99Repetitions Of 4 Steps Of
Beta Oxidation Proper
The
b
-oxidation
proper pathway
is
cyclic
.
4 Steps of Beta Oxidation proper are repeated
Till
whole chain of Fatty acid is
oxidized completely.
Slide100P
roduct
,
2 carbons shorter Acyl -CoA
,
Is
input
to another
round/turn
of the beta oxidation
proper pathway
.
Slide101Acyl CoA molecule released at end of Beta Oxidation
Is the
substrate for the next round
of oxidation
starting with
A
cyl CoA Dehydrogenase
.
Repetition
continues
until
all the carbon atoms of the
original Fatty acyl CoA
are converted to
A
cetyl CoA
.
Slide102The shortened
Acyl
CoA then undergoes another cycle of
beta oxidation
The number of beta oxidation cycles:
n/2-1
, where n – the number of carbon atoms
Slide103Products Of Each Turn
Of
Beta
Oxidation Proper
Slide104Each
turn/cycle
of
β
oxidation
proper
generates
one molecule each of:
FADH
2
NADH+H
+Acetyl
CoA
Fatty
Acyl
CoA
( with 2
carbons shorter each round)
Slide105Steps Of
-Oxidation Proper
of Fatty
Acids Continues
With
A Repeated Sequence
of
4
Reactions
Till
A Long Fatty Acyl Chain Is Completely Oxidized
Slide106For an
oxidation of Palmitic acid
through beta oxidation
7 turns/cycles
of beta oxidation proper steps occur.
Slide107Beta Oxidation
Slide108Fates of the products
of
β
-oxidation of Fatty Acid
Slide109NADH+H
+
and
FADH
2
- are
reoxidized
in
ETC
to
generate ATP
Acetyl CoA
-
Enters
the
Citric
acid
cycle(TCA cycle)
for its
complete oxidation.
Acyl
CoA
–
Undergoes
the
next
turn/cycle
of
β
oxidation proper
.
Slide110Complete Oxidation Of Fatty Acids
Slide111Fatty Acid
β
Oxidation
Acetyl CoA +ATP
TCA Cycle
CO2 +H2O and ATP
Slide112Fatty acid is activated and oxidized via
Beta Oxidation
in specific number of cycles depending upon chain length.
Acetyl CoA
an
end product
of Beta oxidation of Fatty acid
Is further
completely
oxidized
via
TCA cycle
.
Slide1131
Slide114Figure 4. Processing and
-oxidation of P
almitoyl
CoA
matrix side
inner mitochondrial
membrane
1.5
ATP
2.5
ATP
respiratory chain
recycle
6 times
Carnitine
translocase
Palmitoylcarnitine
Palmitoylcarnitine
Palmitoyl-CoA
+ Acetyl CoA
CH
3
-(CH)
12
-C-S-CoA
O
oxidation
FAD
FADH
2
hydration
H
2
O
cleavage
CoA
oxidation
NAD
+
NADH
Citric
acid
cycle
2 CO
2
Slide115Β
-Oxidation
Overall Flow
Slide116MITOCHONDRION
cell membrane
FA
= fatty acid
LPL
= lipoprotein lipase
FABP
= fatty acid binding protein
A
C
S
FABP
FABP
FA
[3]
FABP
acyl-CoA
[4]
CYTOPLASM
CAPILLARY
FA
albumin
FA
FA
FA
from
fat
cell
FA
[1]
acetyl-CoA
TCA
cycle
-oxidation
[6]
[7]
carnitine
transporter
acyl-CoA
[5]
Figure 2. Overview of fatty acid degradation
ACS
=
acyl
CoA synthetase
L
P
L
Lipoproteins
(Chylomicrons
or VLDL)
[2]
Slide117Energetics Of Beta oxidation
Of Palmitate
Slide118Oxidation of Palmitic
Acid
C16
Number
of turns of fatty acid spiral =
8-1 = 7
Cycles
of beta oxidation proper.
Generates
8 Acetyl CoA
Slide119During
Electron Transport and Oxidative
Phosphorylation
Each
FADH2 yield 1.5
ATP
and NADH 2.5
ATP
Slide120Energetics of Fatty Acid Beta Oxidation
e.g. Palmitic (16C):
β
-oxidation of Palmitic acid
will be repeated in
7 cycles
producing
8 molecules of Acetyl COA
.
In each cycle 1
FADH2 and 1 NADH+H
+
is produced and will be transported to the respiratory chain/ETC.
FADH
2
1.5 ATP
NADH + H
+
2.5 ATP
Thus Each cycle of
β
-oxidation
04 ATP
So 7 cycles of
β
-oxidation
4
x 7 =
28 ATP
Slide1211 Acetyl
CoA
Yields
10 ATPs
via
TCA Cycle
Slide122Review ATP Generation –TCA/
Citric Acid
Cycle which
start with Acetyl CoA
Step
ATP
produced
Step
4 (
NADH+H
to
ETC)
2.5 ATP
Step 6 (
NADH+H
to E.T.C.)
2.5 ATP
Step 10
(
NADH+H
to
ETC)
2.5 ATP
Step 8 (
FADH2
to E.T.C.)
1.5 ATP
1 GTP
01 ATP
NET per turn of TCA Cycle
10 ATP
Slide1231 ATP converted to AMP
during activation of
Palmitic
acid to Palmitoyl-CoA
is equivalent to 2ATPs utilized
Slide124Each
A
cetyl COA
which is oxidized completely in citric cycle/TCA cycle gives
10 ATP
Hence 8 Acetyl CoA via TCA cycle
(
8
x 10 = 80 ATP)
2 ATP are utilized in the activation of Fatty acid
Energy gain = Energy produced - Energy utilized
28 ATP + 80 ATP - 2 ATP =
106 ATP
Slide125Thus On Complete Oxidation of
One molecule of Palmitate
106 molecules of
ATP
are generated
Slide126ATP Generation from
Palmitate Oxidation
Palmitoyl CoA + 7 HS-CoA + 7 FAD
+
+ 7 NAD
+
+ 7 H
2
O
8
Acetyl
CoA
+ 7FADH
2
+ 7 NADH + 7 H
+
Net yield of ATP per one oxidized P
almitate
Palmitate (
C
15
H
31
COOH
) - 7 cycles – n/2-1
Slide127ATP generated
8
Acetyl CoA(TCA)
10x8=80
7 FADH
2
7x1.5=10.5
7
NADH
7x2.5=17.5
108
ATP
ATP expended to activate
Palmitate
-2 ATP
Net yield of ATPs with Palmitate Oxidation: 106
ATP
Slide128Total End Products
Of
Beta Oxidation
Of
1 molecule of a Palmitic Acid
Slide129Palmitic
acid
With 7 Turns of
Beta Oxidation Proper
Generates
8
Molecules Of
Acetyl-CoA
7 FADH2+7 NADH+H
+
Slide130Slide131Summary
of one
round/turn/cycle
of
the
b
-oxidation pathway:
F
atty
A
cyl-CoA
+ FAD + NAD
+
+
HS-CoA
+Acetyl-CoA
Fatty
A
cyl-CoA
(2 C less)
+ FADH
2
+ NADH + H
+
Stoichiometry for
Palmitic Acid Oxidation
Slide133Slide134β-Oxidation Proper of Acyl-CoA
Slide135Fatty
acyl
CoA
b
-Oxidation of
Saturated
fatty acids
Slide136Regulation Of Beta Oxidation
Of Fatty Acids
Slide137Lipolysis and
β
O
xidation of Fatty acids are well
regulated
under
Hormonal
influence
.
Slide138Insulin
secretion is
In
Well Fed Condition
Insulin inhibits Lipolysis
of Adipose Fat (TAG) and mobilization of Free Fatty acids
.
Insulin decreases
β
Oxidation of Fatty acids.
Slide139Glucagon In Emergency Condition
When Cellular or Blood Glucose lowers down there is secretion of Glucagon.
Glucagon and Epinephrine
stimulates Lipolysis
in emergency condition.
Slide140Glucagon stimulates the Enzyme Hormone sensitive Lipase
and hydrolyzes depot Fat(TAG).
Glucagon mobilizes Free fatty acids out into blood circulation
Increases
β
Oxidation of Fatty acids.
Slide141Regulation Of
Beta Oxidation Of Fatty Acid
At Two Levels
Carnitine Shuttle
Beta Oxidation Proper
Slide142Transport of Fatty Acyl CoA
from
Cytosol
into Via Carnitine Shuttle
Mitochondrial Matrix
Is a Rate-limiting step
Slide143Malonyl-CoA
Regulates Beta Oxidation
At Carnitine Transport
Level
Malonyl-CoA an intermediate of
Lipogenesis
Is an Inhibitor
of
Carnitine Acyl Transferase I
Slide144Malonyl-CoA is produced from
Acetyl-CoA
by the enzyme
Acetyl-CoA
Carboxylase
during Fatty acid biosynthesis.
Malonyl-CoA
(which is
a
precursor for fatty acid synthesis)
inhibits Carnitine Palmitoyl Transferase I
.
This Control of
F
atty
acid oxidation
is exerted mainly at the step of
Fatty
acid entry
into mitochondria.
Slide145Acyl-CoA Dehydrogenase is Regulatory or
Key
Enzyme
of
Beta Oxidation Of Fatty Acids
Slide146Significance Of Beta oxidation
of a Fatty acid
Slide147Beta oxidation cycles helps in
cleaving and shortening of a long chain Fatty acid
Slide148Oxidation of Beta carbon atom of a Fatty acid
transforms
stronger
bond between alpha and beta carbon atom to a weaker bond
.
Slide149Transformation to
a weaker bond helps in easy cleavage between alpha and beta carbon
During
β
oxidation there is
dehydrogenation of beta carbon atom (CH2 to C=O)
Slide150Hydrogen
atoms
removed during beta oxidation
are
Temporarily
accepted by the
oxidized coenzymes
(FAD and NAD
+
) to
form reduced coenzymes
Reduced coenzymes then
finally enter ETC and get reoxidizedThe byproduct of ETC is ATP
Slide151Thus
Beta oxidation
of Fatty acid
Metabolizes a long chain fatty acid with
liberation of
chemical form of energy
ATP
for cellular activities.
Slide152Summary of
-Oxidation
Repetition of the
-Oxidation C
ycle
yields a succession of
Acetate
units
Palmitic
acid yields
eight
Acetyl-
CoAs
Complete
-oxidation of one
Palmitic
acid yields
106 molecules of ATP
Large energy yield is consequence of the
highly reduced state of the carbon in fatty acids
This makes
fatty
acid
the fuel of choice for migratory birds and many other animals
Slide153Disorders OF Beta Oxidation
Of Fatty Acids
Slide154Deficiencies of
Carnitine
OR
Carnitine Transferase
OR
Translocase
A
ctivity
A
re
Related
to
Disease
S
tate
Slide155Biochemical Consequences of Carnitine Shuttle Defect
Defect in Carnitine shuttle system
No Beta Oxidation of Fatty acids
No ATP generation
All ATP dependent processes will be ceased
Cell deaths
Organ failures
Slide156Carnitine Shuttle Defects
Affects
normal
function of
Muscles
,
Kidney
, and
Heart
.
Slide157Symptoms
include
Muscle
cramping,
during exercise,
severe weakness
and death
.
Muscle weakness
occurs
since
they are related with
Fatty acid oxidation
for long term energy source.
Slide158Management Of Individuals with Carnitine Shuttle Defects
Note people
with
the Carnitine Transporter Defect
S
hould be
supplemented with a
diet with medium chain fatty
acids
Since
MCFAs
do
not require Carnitine shuttle to enter
Mitochondria
.
Slide159Sudden Infant Death Syndrome
(SIDS)
Slide160SIDS
SIDS is a
congenital rare disorder
with an incidence of
1 in 10,000 births
.
Biochemical Defect:
Due to
congenital
defect
of Enzyme
Acyl-CoA
D
ehydrogenase
a regulatory enzyme of
β
Oxidation of Fatty acid.
Slide161Biochemical Consequences
Of
SIDS
Deficiency of Acyl-CoA Dehydrogenase
Blocks
β
Oxidation
of Fatty acid.
Stops liberation
and supply of energy in
form
of ATPs in fasting condition
Leads to unexpected death of an infant.
Slide162Symptoms in defective Beta Oxidation of Fatty acids include:
H
ypoglycemia
Low Ketone
body
production during fasting
F
atty
Liver
H
eart
and/or
Skeletal
muscle defects
C
omplications of pregnancy
S
udden
infant death
(
SID).
Slide163Hereditary deficiency of
Medium Chain Acyl-CoA Dehydrogenase
(MCAD
)
Most
common genetic disease
relating to fatty acid catabolism, has been
linked to SIDS.
Jamaican Vomiting Sickness
Slide165Jamaican Vomiting Syndrome is due to
ingestion of
unripe Ackee fruit
by people in Jamaica
(
Jamaica
-
Country of Caribbean
)
Slide166Ackee Fruit
Slide167Ackee
fruit is rich in
Hypoglycin –A
Hypoglycin
is an inhibitor of
regulatory Enzyme
β
Oxidation Proper
Acyl-CoA Dehydrogenase
.
Slide168Jamaican
Vomiting Disease
leads to
complications
characterized by :
Severe
Vomiting (throwing out)
Hypoglycemia
Water Electrolyte Imbalance
Convulsions
Coma
Death
Slide169Beta Oxidation
Of
Odd Chain Saturated Fatty Acids
Slide170Ingestion of Odd
chain
carbon Fatty
acids are
less
common in human body
.
Odd chain Fatty acids are formed
by
some bacteria in the stomachs
of
ruminants
and the
human colon.
Slide171β
-oxidation of odd chain Saturated Fatty acid occurs
same as even chain Fatty acid
oxidation
Releasing
Acetyl CoA (2C) in every turn
.
Until the final Thiolase cleavage
Which results in a
3 Carbon Acyl-CoA
/
Propionyl-CoA
in last cycle and last step of beta oxidation.
Slide172End Products Of
Odd
Chain Fatty Acid Oxidation
Slide173End
products
of
b
-oxidation of an odd-number
Fatty
acid is
:
Acetyl-CoA(C2)
Propionyl-CoA(C3)
Slide174Fate Of Acetyl-CoA
Acetyl CoA released from beta oxidation of odd chain fatty acid
Enter in TCA cycle
and get
completely oxidized
.
Slide175Fate Of
Propionyl-CoA
OR
Metabolism
Of Propionyl CoA
Slide176Propionyl
CoA
(3C)
An End Product Of Odd Chain Fatty Acid
Is Converted into
Succinyl
CoA (4C)
A TCA
intermediate
Slide177Metabolism Of Propionyl-CoA
Slide178Metabolism of Propionyl-CoA
The Propionyl-CoA is
converted
to
Succinyl-CoA
.
Which is
an
intermediate of TCA/Citric acid cycle
Slide179Propionyl
CoA metabolism is
dependent
on
Two
Vitamin B complex
members:
Biotin
Vitamin
B
12
Special
set of 3
Enzymes
are required
to further
metabolize Propionyl-CoA
to
Succinyl -
CoA
.
Final Product
Succinyl-CoA enters TCA cycle and get metabolized.
Slide181Three
Enzymes
convert
Propionyl-CoA to
Succinyl-CoA:
Carboxylase
Epimerase
Mutase
Slide182Slide183Step1
Propionyl CoA
is
Carboxylated
to yield
D
Methylmalonyl CoA.
Enzyme:
Propionyl CoA Carboxylase
Coenzyme:
Cyto Biotin
An
ATP is required
Slide184Slide185Step2
The
D Methylmalonyl CoA
is racemized to the
L Methylmalonyl CoA
.
Enzyme: Methylmalonyl-CoA Racemase/ Epimerase
Slide186Slide187Step 3
L Methylmalonyl CoA is converted into Succinyl CoA by an intramolecular rearrangement
Enzyme: Methylmalonyl CoA Mutase
Coenzyme of Vitamin B12 :
Deoxy
Adenosyl
Cobalamin
Slide188Slide189Fates Of Succinyl
CoA
Succinyl CoA
Enters TCA cycle
and get metabolized
Serve as
Glucogenic precursor
for Glucose biosynthesis in emergency condition
Used as a
precursor for Heme biosynthesis
Involves in
Thiophorase reaction
of
Ketolysis.
Slide190Slide191Oxidation of Odd-chain Fatty Acids
Conversion of Propionyl-CoA to Succinyl-CoA
Slide192Defects In Propionyl CoA Metabolism
Slide193Deficiency of
Enzyme
Propionyl-CoA Carboxylase
will block the metabolism of Propionyl-CoA.
Accumulates Propionyl-CoA in blood leading to
Propionicacidemia.
Slide194Deficiency
of
Vitamin B Complex members
affects
P
ropionyl CoA metabolism to Succinyl –CoA.
Vitamin B12
deficiency
blocks
the
Mutase reaction
Accumulates L-Methyl Malonyl-CoA
leading to
Methyl Malonylaciduria.
Slide195Alpha Oxidation Of Fatty Acid
OR
Oxidation
Of
Branched-Chain
Fatty
Acid
OR
Phytanic Acid
Oxidation
3,7,11,15-tetramethyl
H
exadecanoic
acid
Slide196S
ource
of
Phytanic acid in
human body
is through ingestion of
animal
Foods.
Phytanic acid
is a
breakdown product of
Phytol
component of plant chlorophyll
.
Slide197Why Phytanic Acid
Does Not Initiate With
Beta Oxidation Process?
Slide198Phytanic acid is a 16 Carbon Branched chain Fatty Acid.
Has Four Methyl branches at odd-number carbons
3,7,11 and 15
.
Which is not
good substrates for
-oxidation
.
Slide199B
ranched
chain Phytanic acid
contains Methyl (CH3)
group
at
β
Carbon atom.
Hence it
cannot get oxidized initially via
β
oxidation
pathway
Slide200In
α
Oxidation of Phytanic acid
Alpha
Carbon atom is oxidized
With the release of one Carbon unit
CO2
at one time.
Slide201Thus initially
Phytanic acid
follows
α
Oxidation
Modify Phytanic acid to Pristanic acid
and
Further present it for
Beta Oxidation process.
Slide202Occurrence Of Alpha Oxidation Of Phytanic Acid
Slide203Predominantly Alpha Oxidation
Of Phytanic Acid
Takes Place in
Endoplasmic Reticulum
of Brain Cells
Also In Peroxisomes
Slide204Mechanism Of Alpha Oxidation Of Phytanic Acid
Slide205Phytanic acid
3,7,11,15-Tetramethyl
H
exadecanoic acid
Alpha oxidation
removes
Methyl groups
at beta carbon.
Later
making
Fatty
acid ready for beta oxidation process.
Slide206Slide207During
α
Oxidation there occurs:
Hydroxylation at
α
Carbon
in presence of Enzyme
Hydroxylase or Monoxygenase .
This reaction is
Vitamin C dependent
forming
α Hydroxy Acyl-CoA.
Slide208α
Hydroxy
Acyl-CoA is then oxidized to
α
Keto Acyl-CoA
.
Ketonic
group at
α
Carbon
atom is decarboxylated
Yielding CO2 molecule
and a Fatty acid with one Carbon atom less.
Slide209Phytanic acid
on alpha oxidation is
converted to Pristanic acid
Which is
further metabolized via beta oxidation process
to generate Propionyl-CoA.
Slide210Products of Phytanic Acid Oxidation
Alpha oxidation of Phytanic acid Generates
Acetyl-CoA
Propionyl-CoA
Isobutryl-CoA
Slide211Disorders Associated
With
Defective
α
Oxidation
Of Phytanic Acid
Slide212Refsums Disease
Slide213Refsums disease
is a
rare
but
severe neurological disorder.
Caused due to
defect in
α
Oxidation
of Phytanic acid
Slide214The Enzyme Defects
D
eficiency
of
Enzyme
Phytanic
acid
α
Oxidase/ Phytanol-CoA Dioxygenase
leads to Refsum's disease.
Autosomal Recessive
Slide215Biochemical Consequence Of Refsums disease Is:
No Oxidation of Phytanic acid
Accumulation of Phytanic acid in Brain cells and Other Tissues
Dysfunction of Brain
Manifesting Neurological disorder
Slide216Slide217Management Of Refsums disease is :
Avoid eating diet containing Phytol /Phytanic acid.
Slide218Omega Oxidation Of Fatty Acids
Slide219Omega Oxidation of Fatty acid is:
Oxidation of Omega Carbon atom (CH3) of a Fatty acid.
Slide220When Does Omega Oxidation
Of Fatty Acid Occurs?
Slide221Omega Oxidation takes place
when there is defect in
β
Oxidation of fatty acid.
Slide222During
ω
Oxidation of Fatty acid
ω
Carbon atom (CH3) of a Fatty acid is
transformed to -
COOH
O
mega
oxidation forms
Dicarboxylic acid
Which
further undergo
oxidation
Form
more short
Dicarboxylic acids
Adipic acid and Succinic acid
Which are more
polar excreted out in Urine.
Slide224ω
-Oxidation
of Fatty acids
Occur in
Endoplasmic Reticulum
of Liver Cells
Slide225Mechanism Of ω
Oxidation
ω
Oxidation of Fatty acid is a
minor alternative oxidative Pathway.
Slide226Omega Oxidation of a Fatty acid takes place with:
Hydroxylation Reaction
Oxidation Reaction
Slide227ω
= Omega
,
last letter in
Greek
alphabet
Slide228Slide229In
ω
Oxidation of Fatty acid
there occurs
Hydroxylation at
ω
Carbon
atom
Converting
into
Primary terminal Alcohol
(-
CH2OH) group
.
This reaction is catalyzed by NADPH+H
+
dependent
Cytochrome P450
system
Next
primary
terminal Alcohol group is
oxidized to form -COOH group
.
Slide230Further
Dicarboxylic
acid generated through Omega Oxidation
undergoes beta oxidation
To
produce short chain Dicarboxylic acids as Adipic acid and Succinic acid
Which are
polar and excreted out through Urine
.
Slide231Significance Of Omega Oxidation
Omega Oxidation
transforms a non polar Fatty acid to polar
Dicarboxylic fatty acid.
Omega Oxidation of fatty acid
facilitates excretion of accumulated fatty acids
due to defective normal
β
Oxidation in
cells
.
Slide232Peroxisomal Oxidation Of
Fatty Acids
Slide233OXIDATION OF FATTY ACIDS IN PEROXISOMES
Peroxisomes
–
Cell organelles
containing
Enzymes
Peroxidase
and
Catalase
These Enzymes
catalyzes
dismutation of
Hydrogen
peroxide
into
water and molecular oxygen
Slide234When
?
Why? How?
Does
Peroxisomal Oxidation
OF
Fatty Acid Occurs?
Slide235Slide236b
-Oxidation
of very long-chain fatty
acids(>C22)
occurs
within
Peroxisomes
initially
Later undergoes
Mitochondrial
β
Oxidation
.
Slide237Carnitine
is involved in transfer of
Very long Chain Fatty
acids
(
VLCFAS
>
C22
)
into
and out of
Peroxisomes
.
Slide238Peroxisomal Fatty acid oxidation is
induced by a high Fat diet with VLCFAs.
To
shortens
VLCFAs into LCFAs
Which are
further degraded by Beta oxidation process
.
Slide239Peroxisomal
-
Oxidation
Similar to
Mitochondrial
-oxidation,
Initial
double bond formation is
catalyzed by
F
lavoprotein
Acyl-CoA
O
xidase
Slide240Slide241Acyl CoA
Oxidase–FAD transfers
electrons to O
2
to yield
H
2
O
2.
Slide242Coenzyme FAD
is e
-
acceptor for
Peroxisomal
Acyl-CoA Oxidase,
which catalyzes
1
st
oxidative step of
pathway
.
Slide243FADH2 generated
at this step instead of transferring
high-energy
electrons to ETC, as occurs in Mitochondrial
beta-
oxidation.
Electrons of
FADH2
directly
go to O
2
at reaction level to
generate H2O2
in Peroxisomes.
Slide244Thus FADH2
generated
in Peroxisomes
by Fatty acid oxidation
do not enter ETC to liberate ATPs
.
Instead
peroxisome
,
FADH
2
generated by fatty acid oxidation by
Acyl CoA Oxidase
is
reoxidized producing Hydrogen
peroxide
.
Slide245FADH
2
+ O
2
FAD + H
2
O
2
Peroxisomal
enzyme
Catalase
degrades H
2
O
2
:
2
H
2
O
2
2 H
2
O +
O
2
These reactions produce
N
o
ATP
.
Slide246Once
Very Long Chain Fatty
acids are reduced in length within the
Peroxisomes
They
may shift
to
M
itochondrial beta oxidation for further catabolism of fatty acids.
Slide247No
ATPs
result from
steps of Peroxisomal
oxidation of VLCFAs.
Slide248Steps of Peroxisomal Oxidation of Fatty acid
does not generate
ATPs
Instead
energy
dissipated
in
form
of heat.
Slide249Many
drugs
commercially available in market for
reducing obesity
Stimulate
P
eroxisomal beta oxidation
Where
Fatty
acids are oxidized without much liberation of calories (ATPs).
Slide250Peroxisomal Oxidation of Fatty acid efficiently takes place in:
Obese persons
Persons taking Hypolipidemic drugs(Clofibrate).
Slide251Slide252Slide253Zellwegers Syndrome
OR
C
erebro
hepato
renal Syndrome
Slide254Peroxisomal
Disorder
Zellweger
Syndrome
Cerebro
-
Hepato
-Renal Syndrome
Slide255Biochemical Causes
Slide256Rare genetic autosomal recessive disorder.
Characterized by
absence of functional Peroxisomes.
Slide257Gene mutations in
PEX Genes
leads to Zellwegers Syndrome.
Slide258Biochemical Alterations
No oxidation
of
very long chain Fatty acids
and
branched chain fatty acids
in
Peroxisomes
Slide259Accumulation
of large abnormal amounts of
VLCFAs
in
Peroxisomes of tissues.
No
normal
function of
Peroxisomes
.
Slide260Progressive degeneration of
Brain/Liver/Kidney,
with
death ~6 month after onset.
Slide261Signs and Symptoms
Defect
in normal function of
multiple organ system.
Impaired
neuronal migration, positioning and
brain development.
Hypomyelination
affecting nerve impulse transmission.
Hepatomegaly
Renal Cysts
Typical
Dysmorphic
facies.
Slide262Diagnosis
Detection of Increased levels of Serum
Very Long Chain Fatty Acids- VLCFAs
Slide263Slide264Oxidation Of Unsaturated
Fatty Acids
Slide265PUFAs
having
double bonds
in their structure
are unstable
.
Double
bonds
are hydrolyzed and
metabolized faster
than
saturated bonds
.
Thus dietary intake of PUFA get readily metabolizedWhich reduces risk of Atherosclerosis.
Slide266PUFAs are less reduced than SFAs
Hence PUFAs are less energetic than SFAs
Slide267Mechanism Of Oxidation Of Unsaturated Fatty Acids
Slide268Initial and later
Oxidation
of PUFAs
is
by
Similar steps of
β
Oxidation
in
parts
, of
saturated bonds
.
Slide269D
ouble
bonds of UFAs are cleaved by
action
of Extra Enzymes:
Isomerase
(
Enoyl CoA Isomerase)
(For odd numbered double bonds MUFAs)
Reductase
(2,4 Dienoyl CoA Reductase)
(For even numbered double bonds PUFAS)
Epimerase
(Converts
D-Isomer
to
L-Isomer
)
Slide270Enoyl CoA Isomerase
handles
odd numbered double bonds
in MUFAs.
2,4 Dienoyl CoA Reductase
handles
even numbered double bonds
in PUFAs.
Slide271Usually natural unsaturated fatty acids have
cis
double bonds.
Which
is
transformed to
trans double bonds
by the action of an
Isomerase .
As
next
enzyme to act is
Enoyl Hydratase ,which acts only on trans double bonds.
Slide272Enoyl-CoA
I
somerase
converts
Cis unsaturated Fatty acids
to
T
rans-
2
Enoyl-CoA
Now
β-oxidation can continue with hydration of trans-
2
-Enoyl-CoA by Enoyl CoA Hydratase
Slide273Oxidation Of
Monounsaturated
Fatty Acids
Oleic
acid, P
almitoleic
acid
Normal
-oxidation for three cycles
C
is-
3
Acyl-CoA
cannot be utilized by
Acyl-CoA
dehydrogenase
Enoyl-CoA I
somerase
converts this to trans-
2
A
cyl
CoA
-oxidation continues from this point
Slide274Slide275Oxidation Of
Polyunsaturated
Fatty Acids
Slightly more complicated
Same as for
Oleic
acid, but only up to a point:
3 cycles of
-oxidation
E
noyl-CoA
I
somerase
1 more round of
-oxidation
Trans-
2
, cis-
4
structure is a
problem.
2,4-Dienoyl-CoA
R
eductase
transform it to odd numbered.
Slide276NADPH dependent 2,4-Dienoyl- Co A Reductase
reduces and merges two double bonds
to form
one Trans at C3
That is then isomerized by Enoyl CoA Isomerase to C2- Trans double bond.
Slide277Slide278Slide279Oxidation of Unsaturated Fatty Acids (Remember they are cis!)
Slide280Slide281b
-oxidation of fatty acids with even numbered double bonds
Slide282The Oxidation of PUFAs
provide less energy
than saturated Fatty acids as they are
less reduced compounds
.
At double bonds the Isomerase act and convert it into
Trans –Enoyl CoA.
This
bypasses the Acyl-CoA Dehydrogenas
e
–FAD linked beta oxidation reaction
.
1.5 ATP less per double bond.